Serotonin (5-HT), a key neurotransmitter in the central nervous system, is believed to play a role in various cognitive functions such as sleep, pain perception, depression, learning and anxiety (Blier et al., 1990; Jacobs and Azmitia, 1992; Mongeau et al., 1997). Neurons of the raphe nuclei which release serotonin have axons that project widely throughout the brain to innervate a variety of nuclei (Tork, 1990). The activity of the raphe nucleus is controlled in part by inhibitory somatodendritic 5-HT1A autoreceptors. The serotonin 1A (5-HT1A) receptor belongs to the seven-transmembrane G-protein coupled receptor superfamily (Hoyer et al., 1994). Its activation inhibits adenylyl cyclase activity, increases K+ conductance causing a decrease in action potential frequency, and decreases the opening of voltage-dependent calcium channels (Penington and Kelly, 1990; Penington et al., 1993; Zgombick et al., 1989). An important function of 5-HT1A autoreceptors in the raphe nuclei is thus to control the frequency of action potential firing. Increase in action potential frequency leads to serotonin release at the cell body, which activates the 5-HT1A receptor to decrease raphe firing and reduce the release of serotonin, as part of a negative feed-back loop (Albert et al., 1996).
Recent studies have suggested that the level of expression of 5-HT1A autoreceptors may play a role in the treatment and possibly the etiology of major depression (Albert et al., 1996; Blier and de Montigny, 1994; Mongeau et al., 1997). Antidepressant compounds (monoamine oxidase inhibitors, tricyclic reuptake inhibitors, and especially serotonin-selective reuptake inhibitors (SSRIs)) act to enhance serotonin release by inhibiting its elimination. These compounds are effective in the treatment of a variety of mental illnesses including major depression, bipolar depression, generalized anxiety disorder, and obsessive compulsive disorder, but 2–3 weeks of treatment are required before clinical improvement may be observed (Charney et al., 1990). Acute treatment with antidepressants to enhance synaptic serotonin levels leads to inhibition of the firing rate of raphe neurons via activation of 5-HT1A autoreceptors, which prevent enhancement of serotonin release (FIG. 2). Chronic (2 weeks) treatment with serotonin uptake inhibitors (eg. fluoxetine) and selective 5-HT1A partial agonists (eg. buspirone) results in a selective downregulation of presynaptic (eg. raphe) but not postsynaptic 5-HT1A receptors (hypothalamus, cortex, hippocampus) (Fanelli and McMonagle-Strucko, 1992; Welner et al., 1989). Desensitization of the 5-HT1A autoreceptor results in restoration of raphe firing rate and enhanced serotonergic neurotransmission (FIG. 2) that correlates with behaviourial improvement induced by antidepressant treatments.
As longterm regulation of the 5-HT1A receptor is implicated in major depression, we have investigated the promoter of the human 5-HT1A receptor gene to characterize and identify specific loci associated with depression. Changes in gene expression persist for days to weeks, and could underlie the down-regulation of 5-HT1A receptors by antidepressant compounds over the 2-week treatment period.